My long-term research goal is to develop effective pharmacological interventions that can alleviate disease progression and improve the quality of life for patients with sickle cell disease (SCD). Approximately 100,000 Americans?primarily African or Hispanic background?suffer from SCD, featured with recurrent episodes of acute vaso-occlusion, hemolytic anemia, and progressive organ damage. The only FDA-approved drug for SCD, hydroxyurea, induces fetal hemoglobin (HbF) production, decreases disease severity, and benefits overall mortality. However, the ability of hydroxyurea to induce HbF is highly variable, with over 50% of patients do not respond to hydroxyurea. There remains a critical and urgent need to identify additional HbF-inducing therapeutic agents. Among a large number of epigenetic mechanisms that have been explored for ?-globin gene reactivation, lysine specific demethylase1 (LSD1) has emerged as an attractive target. Research from our group showed that RN-1, a selective inhibitor of LSD1 significantly stimulated ?-globin gene transcription and reduced disease pathology in a mouse model of SCD. Ongoing study in baboons has confirmed enhanced HbF production by RN-1. However, the mechanism by which LSD1 inhibitor induces HbF is not known. Moreover, recent studies on microRNA (miRNA) have shed lights on the identification of novel HbF inducing agents. Suppression of let- 7a miRNA significantly increased HbF expression in adult human erythroblasts. My own work has identified let- 7 as an epigenetic mechanism in the neuropathogenesis of SCD. Uniquely, my preliminary data suggest that RN-1 improves SCD by mechanisms that involve circulating exosomal miRNA. Therefore, it is scientific compelling to elucidate the intriguing interactions between LSD1 and let-7 miRNA in SCD. While much of the research has been focused on ameliorating clinical severity of SCD, pain can represent as another major therapeutic outcome. SCD is not only characterized by acute exacerbations of pain (acute pain), but also intractable persistent pain throughout a patient's life. Chronic pain is refractory to current medications and represents a significant unmet medical challenge. Increased levels of HbF can alleviate disease symptoms and decrease acute painful episodes. However, scientific evidence for an effect of hydroxyurea on chronic pain in SCD is lacking. In this application, I propose to employ pain as an innovative approach to measure the outcome of inducing HbF. I will test the hypothesis that let-7 miRNA is a novel target of LSD1 to modulate HbF silencing and chronic pain in SCD. By identifying molecular and epigenetic mechanisms of LSD1 and let-7 miRNA in SCD, specific targeting of these mechanisms holds great promise of designing effective therapies that can benefit patients with SCD. Successful completion of the study will not only achieve my training objective to transit to an independent academic investigator, but also build up a strong scientific framework for future research and R01 applications